EP0656349B1 - Dérivés d'aminophénols à activité d'inhibiteurs de phospholipase A2 - Google Patents

Dérivés d'aminophénols à activité d'inhibiteurs de phospholipase A2 Download PDF

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EP0656349B1
EP0656349B1 EP94308932A EP94308932A EP0656349B1 EP 0656349 B1 EP0656349 B1 EP 0656349B1 EP 94308932 A EP94308932 A EP 94308932A EP 94308932 A EP94308932 A EP 94308932A EP 0656349 B1 EP0656349 B1 EP 0656349B1
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alkyl
acid
formula
substituted
alkoxy
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EP0656349A1 (fr
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Hisao C/O Minase Research Institute Nakai
Koumei C/O Minase Research Institute Kamiyasu
Masanori C/O Minase Research Institute Kawamura
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to amidinophenol derivatives, processes for their preparation and pharmaceutical compositions containing them.
  • Phospholipase A 2 is an enzyme which acts on phospholipids existing in cell membrane and hydrolyzes an ester bond at the second position of the phospholipids.
  • PLA 2 Phospholipase A 2
  • membrane-associated PLA 2 and pancreatic PLA 2 .
  • Membrane-associated PLA 2 acts on phospholipids to release arachidonic acid (AA) from the phospholipids.
  • AA arachidonic acid
  • the AA is converted into prostaglandins, thromboxanes and leukotrienes, which are physiologically active substances inducing various inflammatory diseases and allergic diseases.
  • pancreatic PLA 2 degrades phosphoric acid and destroys cell membranes, thereby producing lysolecithin which has strong cytotoxicity. Recently, much importance has been attached to pancreatitis, severity in pancreatitis and multiple organ failure induced by such destructive activity on cell membrane, and it has been more remarkable. Further, it is reported that membrane-associated PLA 2 is also concerned with these diseases.
  • the inhibition of PLA 2 leads to the suppression of the release of AA, a precursor of various physiologically active substances, and therefore, it is considered to be useful for the prevention and/or the treatment of various inflammatory and allergic diseases. Furthermore, it is considered to be useful for the prevention and/or the treatment of pancreatitis, severity in pancreatitis and multiple organ failure due to the inhibition of destructive activity on cell membrane.
  • guanidino containing compounds guanidinobenzoic acid derivatives such as camostat mesylate (code No. FOY-305) of the formula (X) : and nafamostat mesylate (code No. FUT-175) of the formula (Y) : (see Japanese Journal of Clinical Medicine, 48 (1), 165-172, 1990).
  • R 2Z and R 3Z in the formula (Z) hereinbefore depicted can represent NHCO-R 6Z , but the nitrogen atom in the said group is attached directly to a benzene ring, and further R 6Z represents only an alkyl group.
  • R 3 in the compounds of the present invention described hereinafter represents CON(R 7 )(R 8 ) or CON(R 9 )-CH(R 7 )(R 8 ); the carbon atom in the said group is attached to a benzene ring via a group A.
  • the compounds of the present invention therefore have a chemical structure quite different from the compounds of the formula (Z).
  • amidinophenol derivatives of the formula (Z) hereinbefore depicted have an inhibitory activity on PLA 2 , though some guanidinobenzoic acid derivatives (compounds of the formulae (X) and (Y) hereinbefore depicted) were known to have the activity.
  • amidinophenol derivatives of the present invention have an inhibitory activity on PLA 2 .
  • the acid addition salts are preferred.
  • the compounds of the invention may form hydrates: it is to be understood that such hydrates form part of the present invention and that references to the compounds in this specification including the accompanying claims are to be understood as embracing the hydrates.
  • the compounds of the present invention possess inhibitory activity on PLA 2 and, additionally, a strong inhibitory activity on various proteases such as trypsin, plasmin, thrombin and kallikrein, especially on trypsin.
  • alkyl, alkoxy, alkylene, alkenylene and alkynylene groups include straight-chain and also branched-chain ones, and the double bonds in the alkenylene group include E, Z and EZ mixture. Accordingly, all isomers produced by the existence of asymmetric carbon atoms are included in the present invention when e.g. branched-chain alkyl, alkoxy, alkylene, alkenylene and alkynylene exist.
  • the C1-4 alkyl group represented by R 1 , R 2 , R 5 , R 6 and R 12 , and that in R 7 and R 8 , means methyl, ethyl, propyl, butyl and the isomers thereof.
  • the C1-4 alkoxy group represented by R 1 and R 2 means methoxy, ethoxy, propoxy, butoxy and the isomers thereof.
  • the C1-3 alkyl group represented by R 4 means methyl, ethyl, propyl and the isomers thereof.
  • the C2-5 acyl group represented by R 1 and R 2 means acetyl, propionyl, butyryl, valeryl and the isomers thereof.
  • the C1-10 alkyl group represented by R 7 and R 8 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the isomers thereof.
  • the C1-8 alkyl group represented by R 9 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof.
  • the C7-10 phenylalkyl group represented by R 7 , R 8 , R 9 and R 12 means methyl, ethyl, propyl, butyl and the isomers thereof, which are substituted by a phenyl group.
  • the C1-4 alkylene group represented by A means methylene, ethylene, trimethylene, tetramethylene and the isomers thereof.
  • the C1-8 alkylene group represented by R 11 and R 11a means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the isomers thereof.
  • the C2-8 alkenylene group means vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the isomers thereof.
  • the C2-8 alkynylene group means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the isomers thereof.
  • the C2-8 alkylene in which carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, represented by R 11a means thiaethylene (i.e., -CH 2 -S- and -S-CH 2 -), thiatrimethylene (i.e., -CH 2 -CH 2 -S-, -CH 2 -S-CH 2 -, -S-CH 2 -CH 2 -), thiatetramethylene, thiapentamethylene, thiahexamethylene, thiaheptamethylene, thiaoctamethylene and the isomers thereof, or the group in which one of any methylene group in the said thiaalkylene group, is replaced by a phenylene group (e.g., -CH 2 -S-CH 2 -C 6 H 4 -).
  • a phenylene group e.g., -CH 2 -S-CH 2 -C 6 H 4 -
  • the C4-8 alkynylene in which carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene means thiabutynylene (e.g., -S-CH 2 -C ⁇ C-), thiapentynylene (e.g., -S-CH 2 -CH 2 -C ⁇ C-, -S-CH 2 -C ⁇ C-CH 2 - and -CH 2 -S-CH 2 -C ⁇ C-), thiahexynylene, thiaheptynylene, thiaoctynylene and the isomers thereof, or the group in which one of any methylene groups in the said thiaalkynylene group, is replaced by a phenylene group (e.g., -S-CH 2 -C ⁇ C-C 6 H 4 -).
  • a phenylene group e.g., -S-CH 2 -C ⁇ C-C 6 H 4
  • examples of the 7-14 membered, bi- or tri-cyclic hetero ring containing one nitrogen, in R7 and R8, are indole, indoline, quinoline, 1,2,3,4-tetrahydroquinoline and carbazole.
  • the C2-10 alkenyl having one to three double bonds represented by R 7 , R 8 and R 9 , means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, hexatrienyl, heptatrienyl, octatrienyl, nonatrienyl, decatrienyl and the isomers thereof.
  • the C2-10 alkynyl having one or two triple bonds means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, nonadiynyl, decadiynyl and the isomers thereof.
  • the cycloalkyl group represented by R 7 , R 8 and R 9 means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the C1-6 alkyl substituted by C1-4 alkoxy represented by R 7 , R 8 and R 9 means methyl, ethyl, propyl, butyl, pentyl, hexyl and the isomers thereof, which are substituted by methoxy, ethoxy, propoxy, butoxy and the isomers thereof.
  • the compounds of the formula (I), of the present invention may be converted into the corresponding acid-addition salts by known methods.
  • Non toxic and water-soluble salts are preferable.
  • Suitable acid-addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid
  • organic acids such as acetic acid, trifluoro
  • the compounds of formula (I) in which none of R 7 , R 8 and R 9 , in R 3 , represent groups containing COOH or t-butoxycarbonyl i.e., the compounds of the formula (Ia): wherein R 1 , R 2 and A have the same meanings as hereinbefore defined, and R 3a has the same meaning as hereinbefore defined for R 3 , provided that none of R 7 , R 8 and R 9 , in R 3 , represent groups containing COOH or t-butoxycarbonyl, may be prepared by esterification of a compound of the formula (IIa): wherein R 2 , R 3a and A have the same meanings as hereinbefore defined, with a compound of the formula (III): wherein R 1 has the same meaning as hereinbefore defined.
  • the said esterification is known and can be carried out for example:
  • the reactions (1), (2) and (3) hereinbefore described may be preferably carried out in an atmosphere of inert gas (e.g., argon, nitrogen) under anhydrous conditions.
  • inert gas e.g., argon, nitrogen
  • the hydrolysis of the t-butyl ester group may be carried out, for example, by using an organic acid (e.g., trifluoroacetic acid) or an inorganic acid (e.g., hydrochloric acid), or the mixture thereof, in an inert organic solvent (e.g., methylene chloride, chloroform, methanol, dioxane, ethyl acetate, anisole) at a temperature of from 0°C to 90°C.
  • an organic acid e.g., trifluoroacetic acid
  • an inorganic acid e.g., hydrochloric acid
  • an inert organic solvent e.g., methylene chloride, chloroform, methanol, dioxane, ethyl acetate, anisole
  • R 2 , A, and R 31a have the same meanings as hereinbefore defined and R 71a , R 81a and R 91a have the same meanings as hereinbefore defined for R 7 , R 8 and R 9 , respectively, provided that none of R 71a , R 81a and R 91a are groups containing benzyloxycarbonyl, allyloxycarbonyl and propargyloxycarbonyl.
  • R 2 , A and R 32a have the same meanings as hereinbefore defined and R 72a , R 82a and R 92a have the same meanings as hereinbefore defined for R 7 , R 8 and R 9 , respectively, provided that at least one of R 72a , R 82a and R 92a is a group containing benzyloxycarbonyl, allyloxycarbonyl or propargyloxycarbonyl.
  • the compounds of the formula (IIb) may be prepared by methods known per se , for example, by the series of reactions depicted in the following Scheme C.
  • products may be purified in conventional manner.
  • purification may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
  • the compounds of the formula (I), of the present invention have inhibitory activities on PLA 2 and on various proteases such as trypsin, plasmin, thrombin, kallikrein.
  • proteases such as trypsin, plasmin, thrombin, kallikrein.
  • a test compound in various concentration or water 50 ⁇ l
  • the toxicity of the compounds of the present invention is very weak. Therefore, the compounds of the present invention may be considered to be sufficiently safe and suitable for pharmaceutical use.
  • the inhibition on PLA 2 and on various proteases such as trypsin, plasmin, thrombin, kallikrein, especially trypsin in animals including human beings, especially human beings are useful for the prevention and/or the treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.
  • the compounds of the formula (I), of the present invention, non-toxic acid addition salts thereof, or hydrates thereof may be normally administered systemically or partially, usually by oral or parenteral administration.
  • the doses to be administered are determined depending upon e.g. age, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment.
  • the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 1 mg and 100 mg, by parenteral administration (preferably, intravenously) up to several times per day, or continuous administration between 1 and 24 hrs. per day from vein.
  • the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
  • compositions of the present invention When administering of the compounds of the present invention, it is used in the form of solid compositions, liquid compositions or other compositions for oral administration, as injections, liniments or suppositories etc. for parenteral administration.
  • Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules.
  • Capsules include hard capsules and soft capsules.
  • one or more of the active compound(s) is or are admixed with at least one inert diluent (such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate).
  • the compositions may also comprise, as in normal practice, additional substances other than inert diluents: e.g. lubricating agents (such as magnesium stearate), disintegrating agents (such as cellulose calcium glycolate), stabilizing agents (such as lactose), and assisting agents for dissolving (such as glutamic acid, asparaginic acid).
  • the tablets or pills may, if desired, be coated with a film of gastric or enteric material (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with more than two films. Coating may include containment within capsules of absorbable materials such as gelatin.
  • gastric or enteric material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate
  • Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, syrups and elixirs.
  • the compositions may also comprise inert diluents commonly used in the art (e.g. purified water, ethanol). Besides inert diluents, such compositions may also comprise adjuvants (such as wetting agents, suspending agents), sweetening agents, flavoring agents, perfuming agents, and preserving agents.
  • compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s).
  • Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents (e.g. sodium sulfate), isotonic buffer (e.g. sodium chloride, sodium citrate, citric acid).
  • stabilizing agents e.g. sodium sulfate
  • isotonic buffer e.g. sodium chloride, sodium citrate, citric acid.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
  • one more of active compound(s) is or are admixed with at least one of inert aqueous diluent(s) (e.g. distilled water for injection, physiological salt solution) or inert non-aqueous diluent(s) (e.g. propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, POLYSORBATE80 (registered trade mark)).
  • Injections may comprise additional other inert diluents: e.g.
  • preserving agents wetting agents, emulsifying agents, dispersing agents, stabilizing agent (e.g. lactose), assisting agents such as assisting agents for dissolving (e.g. glutamic acid, asparaginic acid).
  • stabilizing agent e.g. lactose
  • assisting agents such as assisting agents for dissolving (e.g. glutamic acid, asparaginic acid).
  • They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions, for example, by freeze-drying, and which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
  • compositions for parenteral administration include endermic ones such as liquids for external use, ointment, and endermic liniments, and suppositories and pessaries for intrarectal administration which comprise one or more of the active compound(s) and may be prepared by per se known methods.
  • the solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations.
  • the following components were admixed in conventional manner.
  • the solution was sterilized in conventional manner, placed 5 ml portion into ampoules and freeze-dried to obtain 100 ampoules each containing 20 mg of the active ingredient.

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Claims (10)

  1. Dérivé d'amidinophénol de formule (I) :
    Figure 00690001
    dans laquelle
    R1 et R2 sont chacun indépendamment :
    (i) hydrogène,
    (ii) alkyle en C1-4,
    (iii) alcoxy en C1-4,
    (iv) acyle en C2-5,
    (v) halogène,
    (vi) nitro,
    (vii) benzoyle ou
    (viii) COOR4 (dans lequel R4 est alkyle en C1-3) ;
    A est une liaison, alkylène en C1-4 ou
    Figure 00690002
    (dans lequel R5 et R6 sont, chacun indépendamment, hydrogène ou alkyle en C1-4) ;
    R3 est :
    Figure 00690003
    ou
    Figure 00690004
    (dans lesquels R7 et R8 sont chacun indépendamment :
    (1) hydrogène,
    (2) phényle,
    (3) phénylalkyle en C7-10,
    (4) phényle ou phénylalkyle en C7-10, chacun étant substitué par un ou deux substituants éventuellement choisis parmi alkyle en C1-4, halogène et R11-COOR12
       (dans lequel R11 est
    [1] une liaison,
    [2] alkylène en C1-8,
    [3] alcénylène en C2-8, ou
    [4] alcynylène en C2-8,
       R12 est
    [1] hydrogène,
    [2] alkyle en C1-4,
    [3] phénylalkyle en C7-10,
    [4] phényle,
    [5] allyle ou
    [6] propargyle),
    (5) alkyle en C1-10,
    (6) alcényle en C2-10 ayant une à trois doubles liaisons,
    (7) alcynyle en C2-10 ayant une ou deux triples liaisons,
    (8) R11a-COXR12
       (dans lequel R11a est
    [1] une liaison,
    [2] alkylène en C1-8,
    [3] alkylène en C2-8 dans lequel un ou deux atomes de carbone dans la chaíne principale sont remplacés par un soufre ou par un soufre et un phénylène,
    [4] alcénylène en C2-8,
    [5] alcénylène en C4-8 dans lequel un ou deux atomes de carbone dans la chaíne principale sont remplacés par un soufre ou par un soufre et un phénylène,
    [6] alcynylène en C2-8, ou
    [7] alcynylène en C4-8 dans lequel un ou deux atomes de carbone dans la chaíne principale sont remplacés par un soufre ou par un soufre et un phénylène,
    X est oxygène ou -NH-, et R12 a la même signification que celle définie ci-dessus),
    (9) alkyle en C1-4 qui est substitué par un hétérocycle bi- ou tricyclique à 7 à 14 chaínons et contenant un azote,
    (10) cycloalkyle en C3-7, ou
    (11) alkyle en C1-6 qui est substitué par alcoxy en C1-4;
    R9 est
    (1) hydrogène,
    (2) alkyle en C1-8,
    (3) phénylalkyle en C7-10,
    (4) alcényle en C2-10 ayant une à trois doubles liaisons,
    (5) alcynyle en C2-10 ayant une ou deux triples liaisons,
    (6) R11-COOR12 (dans lequel R11et R12 ont la même signification que celle définie ci-dessus),
    (7) cycloalkyle en C3-7, ou
    (8) alkyle en C1-6 qui est substitué par alcoxy en C1-4) ;
    à condition que
    (i) un des groupes R7, R8 et R9 représente alkyle en C1-6 qui est substitué par alcoxy en C1-4,
    (ii) R7 et R8 ne représentent pas simultanément hydrogène, et
    (iii) quand un des R7, R8 et R9 représente un groupe contenant un reste t-butoxycarbonyle, les deux autres ne représentent pas des groupes contenant un reste carboxy;
    ou un de ses sels d'addition avec un acide.
  2. Composé selon la revendication 1 de formule (I-A) :
    Figure 00710001
    dans laquelle R1A et R2A sont, respectivement, tels que définis pour R1 et R2 dans la revendication 1;
    R3A est
    Figure 00720001
    ou
    Figure 00720002
    (dans lesquels R7A et R8A sont chacun indépendamment
    (1) phényle ou phénylalkyle en C7-10 chacun étant substitué par un ou deux substituants R11-COOR12 (dans lequel R11 et R12 sont tels que définis dans la revendication 1),
    (2) R11a-COXR12 (dans lequel R11a, R12 et X sont tels que définis dans la revendication 1), ou
    (3) alkyle en C1-6 qui est substitué par alcoxy en C1-4;
    R9A est
    (1) hydrogène,
    (2) R11-COOR12 (dans lequel R11 et R12 sont tels que définis dans la revendication 1), ou
    (3) alkyle en C1-6 qui est substitué par alcoxy en C1-4 ; et les autres symboles sont tels que définis dans la revendication 1,
    à condition que
    (i) au moins un des groupes dans R7A, R8A et R9A représente alkyle en C1-6 qui est substitué par alcoxy en C1-4 et
    (ii) lorsque l'un des groupes R7A, R6A et R9A représente un groupe contenant un reste t-butoxycarbonyle, les deux autres ne représentent pas des groupes contenant un reste carboxy ;
    ou un de ses sels d'addition avec un acide.
  3. Composé selon la revendication 1 ou 2, qui est un sel d'addition avec un acide.
  4. Composé selon la revendication 1, 2 ou 3, dans lequel R3 est
    Figure 00730001
    dans lequel R7 et R8 sont tels que définis dans la revendication 1.
  5. Composé selon la revendication 1, 2 ou 3, dans lequel R3 est
    Figure 00730002
    dans lequel R7, R8 et R9 sont tels que définis dans la revendication 1.
  6. Composé selon l'une quelconque des revendications précédentes, dans lequel l'un des R7 et R8 est
    (1) R11a-COXR12 (dans lequel R11a, R12 et X sont tels que définis dans la revendication 1), ou
    (2) alkyle en C1-6 qui est substitué par alcoxy en C1-4 ; et
    R9 est
    (1) R11-COOR12 (dans lequel R11et R12 sont tels que définis dans la revendication 1), ou
    (2) alkyle en C1-6 qui est substitué par alcoxy en C1-4.
  7. Composé selon la revendication 1, qui est le
    N-2-éthoxycarbonyléthyl-N-3-méthoxypropylamide de l'acide p-(p-amidinophénoxycarbonyl)-α-méthylcinnamique,
    N-éthoxycarbonylméthyl-N-3-méthoxypropylamide de l'acide p-(p-amidinophénoxycarbonyl)-α-méthylcinnamique,
    N-1,1-bis(éthoxycarbonyl)méthyl-N-3-méthoxypropylamide de l'acide p-(p-amidinophénoxycarbonyl)-α-méthylcinnamique,
    N-t-butoxycarbonylméthyl-N-3-méthoxypropylamide de l'acide p-(p-amidinophénoxycarbonyl)-α-méthylcinnamique,
    N-carboxyméthyl-N-3-méthoxypropylamide de l'acide p-(p-amidinophénoxycarbonyl)-α-méthylcinnamique, ou
    N-éthoxycarbonylméthyl-N-2-méthoxyéthylamide de l'acide p-(p-amidinophénoxycarbonyl)-α-méthylcinnamique.
  8. Procédé de préparation d'un composé selon la revendication 1 ou d'un de ses sels d'addition avec un acide qui comprend :
    (A) lorsqu'aucun des groupes R7, R8 et R9 ne représente des groupes contenant un reste COOH ou t-butoxycarbonyle, l'estérification d'un composé de formule (IIa) :
    Figure 00740001
    dans laquelle R2 et A sont tels que définis dans la revendication 1 et R3a est tel que défini pour R3 dans la revendication 1, à condition qu'aucun des groupes R7, R8 et R9 ne représente des groupes contenant un reste COOH ou t-butoxycarbonyle, avec un composé de formule (III) :
    Figure 00740002
    dans lequel R' est tel que défini dans la revendication 1;
    (B) lorsqu'au moins un des groupes R7, R8 et R9 représente un groupe contenant un reste t-butoxycarbonyle et les deux autres ne représentent pas des groupes contenant un reste COOH, l'amidification d'un composé de formule générale (IIb)
    Figure 00740003
    dans laquelle les différents symboles sont tels que définis dans la revendication 1, avec un composé de formule (IIIb) :
    Figure 00750001
    dans laquelle R7b, R8b et R9b sont, respectivement, tels que définis dans la revendication 1 pour R7, R8 et R9, à condition qu'au moins un des groupes R7b, R8b et R9b représente un groupe contenant un reste t-butoxycarbonyle et les autres ne représentent pas des groupes contenant un reste COOH ; ou
    (C) lorsqu'au moins un des groupes R7, R8 et R9 représente un groupe contenant un reste COOH et les autres ne représentent pas des groupes contenant un reste t-butoxycarbonyle, l'hydrolyse du groupe t-butoxycarbonyle d'un composé de formule (Ib)
    Figure 00750002
    dans laquelle R1, R2 et A sont tels que définis dans la revendication 1 et R3b est tel que défini ci-dessus,
    et, éventuellement, la conversion d'un composé de formule (I) ainsi obtenu en l'un de ses sels d'addition avec un acide.
  9. Composition pharmaceutique qui comprend, en tant que substance active, un dérivé d'amidinophénol de formule (I) décrit dans la revendication 1, ou un de ses sels d'addition avec un acide, avec un support ou enrobage pharmaceutiquement acceptable.
  10. Composé de formule (I) ou un de ses sels d'addition avec un acide, pour une utilisation dans la préparation d'une composition pharmaceutique pour la prévention et/ou le traitement d'un état, qui peut être amélioré par administration d'un inhibiteur de PLA2 ou d'un inhibiteur de protéase.
EP94308932A 1993-12-03 1994-12-01 Dérivés d'aminophénols à activité d'inhibiteurs de phospholipase A2 Expired - Lifetime EP0656349B1 (fr)

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JP30404893 1993-12-03
JP304048/93 1993-12-03

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EP0656349B1 true EP0656349B1 (fr) 1998-04-08

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KR100226619B1 (ko) 1994-09-20 1999-10-15 우에노 토시오 아미디노페놀 유도체
KR20000005312A (ko) 1996-04-10 2000-01-25 오노 야꾸힝 고교 가부시키가이샤 트립타아제 억제제 및 신규 구아니디노 유도체
CA2265996A1 (fr) 1996-09-26 1998-04-02 Roger Aki Fujimoto Acrylamides substitues par de l'aryle ayant une activite antagoniste du recepteur leucotriene b4 (ltb-4)
WO2000051625A1 (fr) * 1999-03-05 2000-09-08 The Trustees Of University Technology Corporation Inhibiteurs d'activite de serine protease, methodes et compositions de traitement de virus de l'herpes
US6489308B1 (en) 1999-03-05 2002-12-03 Trustees Of University Of Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions
US6849605B1 (en) * 1999-03-05 2005-02-01 The Trustees Of University Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of viral infections
AU3731400A (en) 1999-03-05 2000-09-21 Trustees Of University Technology Corporation, The Methods and compositions useful in inhibiting apoptosis
US20040220242A1 (en) * 2003-05-02 2004-11-04 Leland Shapiro Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide induced clinical conditions
PL2520654T3 (pl) 2003-08-26 2017-08-31 The Regents Of The University Of Colorado, A Body Corporate Inhibitory aktywności proteazy serynowej i ich zastosowanie w sposobach i kompozycjach do leczenia zakażeń bakteryjnych
US7671057B2 (en) * 2004-11-08 2010-03-02 Ono Pharmaceutical Co., Ltd. Therapeutic agent for type II diabetes comprising protease-inhibiting compound
WO2008058167A2 (fr) * 2006-11-07 2008-05-15 Case Western Reserve University Méthodes de traitement de troubles associés à l'activation du complément
GB2445920A (en) * 2007-01-25 2008-07-30 Mucokinetica Ltd Amidino compounds for treatment of respiratory disease
EP2419402B1 (fr) * 2009-04-17 2016-08-31 Merz Pharma GmbH & Co. KGaA Synthèse de mésylate de 1-amino-1,3,3,5,5-pentaméthylcyclohexane
CN102225903B (zh) * 2011-04-21 2014-11-26 任建东 脒基胍基取代芳杂环类化合物的合成方法及其用途
CN102491921A (zh) * 2011-12-13 2012-06-13 苏州瑞辉生物医药研发中心有限公司 一种4-胍基苯甲酸（4-甲氧甲酰基）苯酯甲烷磺酸盐的制备方法

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DK0656349T3 (da) 1998-06-02
CA2137106C (fr) 2000-02-08
EP0656349A1 (fr) 1995-06-07
US5514713A (en) 1996-05-07
CA2137106A1 (fr) 1995-06-04
KR0185678B1 (ko) 1999-05-15
TW419454B (en) 2001-01-21
DE69409471T2 (de) 1998-08-27
DE69409471D1 (de) 1998-05-14
ES2115887T3 (es) 1998-07-01
ATE164834T1 (de) 1998-04-15
CN1035998C (zh) 1997-10-01
CN1110679A (zh) 1995-10-25

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